Improving survival and reducing side effects in Hodgkin lymphoma

Dr. Oliver Press, shown here in his lab at Fred Hutchinson Cancer Research Center, led a clinical trial in advanced Hodgkin lymphoma showing how PET imaging can be used to tailor treatment.Fred Hutch News Service

A new study published Monday found evidence that patients with advanced Hodgkin lymphoma are more likely to go into remission when their chemotherapy regimen is guided by imaging partway through treatment. The strategy also reduced toxic side effects for many patients.

“The outcome of this large study was very encouraging and suggested that this approach could maximize cure rates for advanced Hodgkin lymphoma while minimizing toxicities for the majority of patients,” said lead study author Dr. Oliver Press, a lymphoma physician-scientist at Fred Hutchinson Cancer Research Center and the University of Washington.

The trial was the first study of its kind in adult Hodgkin lymphoma patients. Its results were published today in the Journal of Clinical Oncology.

The researchers used imaging after two cycles of a standard chemotherapy to look for an indicator of aggressive tumor cells in lymph nodes. If the scan was positive for signs of these cells, participants were switched to a more intensive and more toxic regimen, which boosted their survival over that seen in previous studies using standard chemotherapy. Patients with negative scans stayed on the standard, less-toxic regimen.

Both Press and the University of Rochester’s Dr. Jonathan Friedberg, the senior author on the study, said that they now use this response-adapted therapy strategy to guide their care of advanced lymphoma patients.

Pursuing a 'balanced' chemo approach

For many years, the standard chemotherapy regimen for Hodgkin lymphoma in the U.S. has been a four-drug combination called ABVD, which cures seven of every 10 patients with advanced (stage 3 or 4) disease.

The more toxic chemo regimen, known as eBEACOPP, was developed in Germany in the 1990s. Results from studies in that country suggested that it might cure more patients than ABVD — but at a cost. Many patients who receive eBEACOPP become infertile, a huge blow to the young adults who make up the bulk of Hodgkin patients. Heart damage and even second cancers are other possible side effects of the eBEACOPP regimen.

This places Hodgkin lymphoma in a special situation, Friedberg said, for researchers to develop a response-adapted therapy that both improves cure rates and decreases toxicities by directing aggressive therapy to only those patients who need it.

“Hodgkin lymphoma is one of the examples of a disease that [response-adapted therapy] makes the most sense in. Because we’re already curing a lot of patients with Hodgkin lymphoma, it suggests that there’s a subset of patients [in whom] we’d like to de-escalate treatment to limit toxicity, and also for that smaller fraction of people whom we’re not curing, to escalate treatment,” said Friedberg, who is the director of the James P. Wilmot Cancer Institute at the University of Rochester Medical Center and chair of the lymphoma committee at SWOG, the cancer clinical trials network that managed this study.

The study used a type of positron emission tomography, or PET, scan that visualizes a sugar molecule with a radioactive label as it’s taken up by cells in the lymph nodes. Highly metabolically active tissues — like aggressively growing tumors — take up a large amount of the sugar, called fluorodeoxyglucose, and glow brightly on a scan, Press said.

Two fluorodeoxyglucose PET scans of one trial participant. In a pre-treatment scan (left), sites of lymphoma in the neck, chest and abdomen glow bright orange. An image taken after two rounds of the standard chemotherapy regimen, ABVD (right), shows an excellent response to therapy. As a result, the participant continued on the less-toxic ABVD, and was spared the side effects of eBEACOPP, a more toxic regimen.Courtesy of Dr. Oliver Press (used with participant consent)

According to previous studies, the result of the PET scan partway through treatment with ABVD is associated with the eventual outcome of the therapy. Patients with advanced disease whose scans were positive after two cycles of ABVD were much more likely to see their disease get worse within two years of completing treatment; just 15 to 30 percent of these patients experienced what scientists call two-year progression-free survival.

The researchers aimed to boost the percentage of these high-risk patients who survived two years without their disease progressing to at least 48 percent by switching them into eBEACOPP instead. In contrast, patients whose imaging suggested they were likely to be cured by the standard ABVD could be spared eBEACOPP’s side effects.

The team also hoped that response-adapted therapy would increase the progression-free survival of the entire group of patients on the trial to 78 percent.

On this prospective study, 331 patients received fluorodeoxyglucose-PET scans after two rounds of ABVD. The scans were positive for highly metabolically active cells in 60 participants, who were then offered six cycles of the more toxic eBEACOPP regimen. Participants who had negative scans continued with four more cycles of the traditional ABVD regimen.

Of the 319 participants who completed their assigned chemo regimens under the study protocol, the calculated two-year progression-free survival was 79 percent, exceeding the researchers’ 78-percent goal.

And while the team had aimed to increase two-year progression-free survival in the higher-risk cohort to around half, progression-free survival in this group jumped to almost two-thirds (64 percent).

“It’s very clear that [eBEACOPP] is a toxic regimen, so in our study, only about 20 percent of patients needed to get that regimen, whereas in Germany, all of the patients are getting that regimen,” Friedberg said, “which I think is the balance, the appeal, of our approach.”

First study of many

As a Phase 2 study without a control arm, the trial is not the so-called gold-standard of medical research, a Phase 3 randomized trial. Whether the results of this single trial will change clinical practice in the lymphoma field as a whole “is in the eye of the beholder,” Press said. “We ultimately would like a Phase 3 study.”

Dr. Julie Vose, a lymphoma specialist who was not an investigator on this trial, said that the study was “very well-designed” and its results are promising. “If we can try to choose just the patients who really need the BEACOPP regimen, which has higher toxicity, that is a benefit to all our Hodgkins patients,” she said.

Vose had enrolled patients on the trial, which had a study site at the University of Nebraska Medical Center, where she is chief of the oncology/hematology division.

Press, Friedberg and their colleagues are not the only team of investigators studying response-adapted therapy in advanced lymphoma. Several other research groups worldwide are also carrying out Phase 2 and 3 trials, and their final results have not yet been released. Press thinks that as the results from all these studies are published, lymphoma specialists around the world may consider adopting some form of PET-guided response-adapted therapy to treat their stage 3 and 4 Hodgkin lymphoma patients.

“If there are two Phase 2 studies side by side showing similar results, I think a lot of physicians will want to change practice,” he said. The investigators will continue to gather follow-up data on participants, including information about long-term survival and side effects, he said.

Vose, for example, said that she and her colleagues do not currently use the response-adapted therapy strategy tested in this new study as a routine part of their Hodgkin lymphoma practice. Instead, she uses a risk-scoring system known as the International Prognostic Score, first published in 1998, to assign Hodgkin lymphoma patients at diagnosis to a chemotherapy regimen (high-score patients are assigned to eBEACOPP). She said that she would consider adopting this trial’s PET-based response-adapted therapy in the clinic after the publication of longer-term follow-up data and data from a larger number of patients assigned to eBEACOPP after a positive PET scan.

A cooperative effort

This trial was a massive collaborative effort, involving three large clinical trials groups supported by the National Cancer Institute. The trial was managed by SWOG, a cancer clinical trials group with 12,000 members worldwide currently based at the Knight Cancer Institute at Oregon Health & Science University. Trial participants were also enrolled through the Alliance for Clinical Trials in Oncology and the ECOG-ACRIN Cancer Research Group.

The trial has been a long time coming: Its moniker is “SWOG S0816,” and the “08” refers to 2008, the year its protocol was written. The first participant was enrolled in 2010. With the intergroup cooperation under Press’ leadership, however, the investigators were able to enroll participants quickly once the trial opened, Friedberg said.

Cooperation “is the direction that the lymphoma groups are moving in nationally,” Friedberg said. “We realized that for us to get the study done in a reasonable period of time, we needed all of the adult cooperative groups to collaborate and not compete.”

Susan Keown is a staff writer at Fred Hutchinson Cancer Research Center. Before joining Fred Hutch in 2014, Susan wrote about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at skeown@fredhutch.org or follow her on Twitter at @sejkeown.

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